New assay platforms and analysis techniques are increasing the speed and sample throughput for likely new drug candidates. Sean Ottewell reports.
ForteBio, a division of Pall Life Sciences and a leading supplier of instrumentation for accelerated drug discovery and development, has launched the Octet HTX system - the new flagship member of the Octet line of label-free interaction analysis systems. The new system addresses the acute industry need for increased analysis speed and sample throughput when characterising large numbers of therapeutic candidates.
Octet systems provide novel insights into drug-target binding interactions, insights that are used to fine-tune the affinity and specificity of drug molecules. The Octet HTX instrument performs kinetic analysis of up to 96 binding interactions simultaneously (Fig. 1), a capability offered by no other stand-alone label-free platform, according to the company.
The system offers dramatic time savings for researchers studying large panels of drug candidates, and provides innovative data analysis tools for developers of monoclonal antibodies and other biotherapeutic entities. In addition, the Octet HTX performs full 96-well plate determinations of protein concentrations in as little as two minutes.
“The need for higher analytical throughput is a central theme with our pharmaceutical and biopharm customers,” noted Robert Wicke, general manager at Pall’s ForteBio division. “We believe researchers will be delighted by the Octet HTX system. The HTX system was engineered for speed while maintaining peak performance, and will directly address critical bottlenecks in the drug development process.”
The BioSeek division of DiscoveRx says it also has released an industry first – a primary human cell-based assay platform for oncology research. Consisting of primary human cell-based tumour-host model systems, this new BioMAP panel enables researchers to easily assess the phenotypic impact of candidate compounds on tumour microenvironment biology in order to better predict in vivo drug activities and forecast potential clinical outcomes with respect to drug efficacy and safety.
“These oncology-focused BioMAP systems will support predictive and physiologically relevant cancer compound development from early discovery through pre-clinical development stages,” said Ellen Berg, scientific director and general manager of BioSeek. “They capture human tumour-host activities that can be modulated by a number of clinically relevant mono-therapies as well as drug combinations involving small molecule chemotherapeutics and biologics. Such BioMAP models recapitulate complex interactions between tumour cells, stromal and/or vascular tissue and recruited, infiltrating immune cells to the tumour.”
Despite a fair number of cancer drugs gaining approval for clinical use, late-stage compound attrition still remains a major issue in anticancer drug development. A critical need remains for pre-clinical models that can serve as better predictors of success in clinical trials.
Scientific evidence is mounting that combination therapies using previously approved oncology drugs can be more efficacious, safe and successful than traditional mono-therapies, making the need for predictive in-vivo models more apparent. By virtue of the fact that the two compounds selected for combination therapy would have been developed independently, determining the appropriate therapeutic dosing for such combinations also continues to be technically challenging. The ability to test drug combinations in predictive models such as BioMAP can support the testing of pre-clinical strategies involving both development compounds and approved drugs.
Inside an anti-viral
The first study of interactions between a common clinical inhibitor and the HIV-1 protease enzyme has been carried out by an international team with members from the US, Britain and France using neutrons at the Institut Laue-Langevin (ILL) in Grenoble, France. It provides medical science with the first true picture of how an antiviral drug used to block virus replication actually works, and critically how its performance could be improved. The findings, reported in the Journal for Medicinal Chemistry, and the neutron techniques demonstrated at the ILL, will provide the basis for the design of a new generation of more effective pharmaceuticals to address issues such as drug resistance.
HIV-1 protease is essential in the life-cycle of HIV where it breaks polypeptide chains to create proteins used for replication and producing new infectious virus particles. Its key role makes it one of the most studied enzymes in the world. For the past 20 years scientists have used highly intense x-rays to investigate the best way to target and block the protease’s role in spreading the virus.
However, this form of analysis has limitations. The strongest bonds between the enzyme and an inhibitor are usually relatively weak hydrogen bonds, yet hydrogen atoms are virtually invisible to x-ray analysis, leaving scientists to speculate as to how this binding takes place.
To address this uncertainty, scientists from Georgia State University, Purdue University and Oak Ridge National Laboratory in the USA and Harwell Oxford in Great Britain used neutrons at the ILL to analyse this binding. Neutrons are highly sensitive to lighter elements, allowing the team to identify the positions of every hydrogen atom involved in the system for the first time, and see which were involved in bonding. The inhibitor studied was Amprenavir (APV), first approved for clinical use in 1999, and experiments were carried out on the LADI-III (quasi-Laue neutron diffractometer) instrument at the ILL.
The neutron studies revealed a very different picture to that inferred from the x-ray studies which had overplayed the importance of many of the hydrogen bonds. In fact the team found only two really strong hydrogen bonds between the drug and the HIV enzyme.
While this might seem concerning, it actually presents drug designers with a set of new potential sites for the improvement of the drug’s surface chemistry to significantly strengthen the binding, thereby increasing the effectiveness of the drugs and reducing the necessary dosages.
Based on their new understanding the team proposed a number of next steps to make these improvements, including: replacing weaker bonds with a greater number of stronger hydrogen bonds; and improving the strength of the existing hydrogen bonds.
Matthew Blakeley of the Institut Laue-Langevin said: “This study perfectly illustrates the benefits of neutrons in drug design due to their unique sensitivity to hydrogen atoms.”
Toxicity screening
In another development, Eurofins Scientific has signed an agreement with GE Healthcare for the exclusive right to offer GE Healthcare’s Cytiva Cardiomyocytes for drug discovery and early development cardio toxicity screening services.
The agreement allows Eurofins Panlabs to provide a novel offering for an early predictive measure of cardiac toxicity and function in a cost-effective and time-efficient manner compared to current expensive and time-consuming animal testing models. The initial range of cardiotoxicity screening services covered by the exclusive right will be expanded during the term of the agreement.
In drug development, up to three quarters of toxicity problems remain undetected until preclinical or later stages. Cardiotoxicity and hepatotoxicity are common causes of drug safety liabilities and withdrawal of drugs during development. The availability of more biologically relevant and predictive assays and cell models is key to helping improve the success rate and reducing the cost of the drug discovery and development process.
GE Healthcare is pioneering the development of human cell-based models such as Cytiva Cardiomyocytes, which provide a biologically relevant alternative to current cell models and primary cells for predictive cardiotoxicity testing.
Eric Roman, general manager of research and applied markets, GE Healthcare Life Sciences, said: “The agreement with Eurofins Panlabs will help realise our vision of bringing the benefits of human cell-based assays and models to pharmaceutical and cell science research. Cardiotoxicity is a common cause of late-stage drug failure, so it’s vital that developers have access to the right tools to help reduce this high attrition rate and to help increase patient safety.”
Warwick wins award for Chagas hunt
Domainex, a drug discovery company specialising in translational research support, has announced that the recipient of its first Discovery STAR award is professor Vilmos Fulop of the University of Warwick.
The award will give Fulop access to Domainex’s drug discovery capabilities to support his research for a much-needed new treatment for Chagas disease - a potentially life-threatening disease. Also known as American trypanosomiasis, Chagas disease causes upwards of 14,000 deaths annually. It is caused by the protozoan parasite Trypanosoma cruzi.
“Domainex received many strong applications to its Discovery STAR award scheme, but professor Fulop’s project stood out as he had all the elements needed to start a drug discovery project in this area of unmet medical need,” said Eddy Littler, ceo of Domainex, “We very much look forward to helping professor Fulop to identify inhibitors of his drug target, and hope that in doing so he will be able to access further funding that will support our joint efforts towards finding a new cure for this terrible disease.”
The company will provide Fulop with expert drug discovery guidance and exclusive access to its LeadBuilder virtual hit screening technology. Following the identification of hits using this approach, Fulop, who has been working with the University of Warwick’s innovation support team Warwick Ventures to take forward his research, will be looking for additional funding to progress his work to identify potential new drug candidates against Chagas disease.
